The principal investigator (P.I.), together with Dr. Boyd Hartman, discovered that tricyclic antidepressants increase blood: brain barrier permeability to diffusion-limited substances. In the previous grant, this effect was found to be dependent upon an intact central adregenergic system (CAS). Mianserin, a novel antidepressant which binds to both alpha-one and alpha-two adrenergic receptors, was also found to alter barrier permeability; whereas, antipsychotic drugs (dopamine receptor blockers) had no effect. Moreover, CO2 administration which increases the firing rate of the CAS was found to increase barrier permeability. This phenomenon was attenuated by pretreatment with the amine depletor, tetrabenazine (TBZ). To pursue this work, the P.I. and colleagues developed several small animal techniques to simultaneously measure barrier permeability and cerebral blood flow (CBF). In this grant, the P.I. will further examine neural modulation of barrier permeability and CBF and its relationship to cerebral energy utilization. Pursuing the anatomy underlying the CO2 effect and the mianserin and TBZ effect, the P.I. will assess the consequences of each of the following on CO2-induced changes in barrier permeability: (a) specific deletion of each biogenic amine system separately, (b) unilateral and bilateral lesions of the locus coeruleus, and (c) intracerebroventricular administration of selective adrenergic and serotonin receptor active drugs. We will determine the role of vasopressin in mediating CO2-induced changes in barrier permeability. To determine whether the ability to alter barrier permeability is a characteristic of antidepressant medications or is a more general pheomenon, we will assess effects of novel antidepressants and other drug classes. To further understand the biological import of these barrier changes, we will use ion-sensitive electrodes to examine concomitant changes in the extracellular space and will examine barrier changes to highly diffusion-limited substances. We will simultaneously use in vivo electrophysiological and electrochemical techniques together with barrier permeability and CBF measurements to study the CAS from cell body firing, neurotransmitter release, and end-organ response in the same animal to physiological stimuli.